The majority of pharmaceuticals are derived from natural products either directly or indirectly. However, the pipeline to new natural products has been drying up over the last decades as the technologies became less amenable to high- throughput screening and as finding new natural products became increasingly difficult. Substantial progress has been made in these areas by numerous labs, but there are still gaps in technology and in basic understanding of natural product sources. In this project, we will provide new methods and data to help fill these remaining gaps. In addition, we will build natural product compound libraries for screening at NIH and at the University of Wisconsin. The new methods include more rapid, automated, and integrated techniques for extraction, purification, and dereplication of natural products. Basic studies of natural product sources using marine symbiotic bacteria are aimed at answering questions about the most fruitful places to find new natural product producers and about methods to obtain these promising bacteria. These biological and chemical studies are synergistic and will provide the first large, ordered set of data linking cultivated symbiotic bacteria to chemistry in whole animals. The resulting methods are designed to be widely useful in multiple labs and to help in the development of broadly shared platforms for dereplication. The resulting libraries of natural products will be used in a variety of screens at established, high-throughput centers at NIH and U. Wisconsin. We will pursue promising leads as potential new pharmaceuticals. PUBLIC HEALTH RELEVANCE: We will develop new methods for the rapid discovery of bioactive natural products and provide new data about sources of natural products that enable drug discovery. We will also provide libraries of natural products for screening. These results will have a large impact on natural products sciences because of new methods and knowledge. The human health impact will result from these new methods and potentially from new therapeutic small molecules discovered in the course of the project.